Abstract
Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest. Using postmortem FFPE tissue blocks (range, 5–72 blocks; median, 30 blocks) for each of 27 patients with progressive MS, we assessed the relationship between meningeal inflammation, the extent of subpial cortical demyelination, and the state of subcortical WM lesional activity. Meningeal accumulations of T cells and B cells, but not myeloid cells, were spatially adjacent to subpial cortical lesions, and greater immune cell accumulation was associated with larger subpial lesion areas. Patients with a higher extent of meningeal inflammation harbored a greater proportion of active and mixed active/inactive WM lesions and an overall lower proportion of inactive and remyelinated WM lesions. Our findings support the involvement of meningeal lymphocytes in subpial cortical injury and point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical WM.
Highlights
Subpial cortical lesions have emerged as an important component of multiple sclerosis (MS) pathology [1,2,3,4,5,6,7]
To assess the extent of meningeal inflammation and its relationship with cortical subpial demyelination, the density of meningeal lymphocytes and their topographic association with subpial demyelination were analysed in formalin-fixed paraffin-embedded (FFPE) tissue blocks dissected from the supratentorial cortex of 27 MS cases compared to 9 controls
Similar to other studies that have demonstrated a correlation between the presence of immune cell aggregates in the MS meninges and demyelination in the adjacent subpial brain compartment [9, 11, 20, 25], when comparing areas of subpial grey matter lesions (GML) to normal appearing grey matter (NAGM) within patients (Supplemental Fig 2), we found that T and B cell infiltrates were selectively enriched in areas of the meninges that were adjacent to subpial lesion areas compared to NAGM in the MS group with a high count of meningeal lymphocytes (Fig 1b-g and Supplemental Fig 3)
Summary
Subpial (type III) cortical lesions have emerged as an important component of multiple sclerosis (MS) pathology [1,2,3,4,5,6,7]. While presence of meningeal inflammation has not been found to relate to either the number of white matter lesions [9] or the extent of white matter demyelination (measured as % demyelination of total white matter in whole brain coronal slices) [20], how subpial cortical injury associated with meningeal inflammation may relate to white matter lesion activity remains unknown Such a relation is of interest, in view of recent pathological findings showing that substantial lesion activity in patients with progressive MS [30]. We investigated the correlation between the extent of meningeal T cell, B cell and myeloid cell accumulation and associated subpial demyelination with subcortical white matter lesion activity, measured as proportion of active, mixed active/inactive, inactive and remyelinated white matter lesions derived from all available archived formalin-fixed paraffin-embedded tissue blocks (range, 5-72 blocks; median, 30 blocks) for each of 27 progressive MS patients collected at rapid autopsy from the Netherlands Brain Bank. While the relationship between grey matter subpial lesions and meningeal inflammation is already appreciated [9, 11, 20, 25], our data connect some aspects of white matter pathology with lymphocyte residence in the subarachnoid space in progressive MS
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